Update on Antibiotics for Infection Control in Cystic Fibrosis

Stephen Kirkby; Kimberly Novak; Karen McCoy

Expert Rev Anti Infect Ther. 2009;7(8):967-980.

Abstract and Introduction

Abstract

Cystic fibrosis pulmonary disease is characterized by chronic and recurrent infection, airway inflammation, bronchiectasis and progressive obstructive lung physiology. Advances in the treatment of common airway pathogens such as Pseudomonas aeruginosa have led to a marked improvement in overall survival. However, antibiotic treatment options are often limited by multidrug resistance, potential toxicities and treatment burden to individual patients. While appropriate anti-infective therapy reduces bacterial density in the airways and may result in clinical improvement, true eradication of airway infection is seldom achieved except for early-stage infections. This review summarizes current approaches for acute and chronic anti-infective therapy in cystic fibrosis.

Introduction

Cystic fibrosis (CF) is the most common fatal genetic disease affecting Caucasian populations worldwide. This autosomal recessive disorder is caused by abnormalities in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which regulates chloride ion transport across cell membranes. Dysfunctional or insufficient levels of the CFTR protein are believed to result in the development of thick and viscous mucus in many organ systems. The respiratory tract is often the most severely affected system, and pulmonary disease is characterized by chronic and recurrent infection, inflammation and the development of bronchiectasis. Respiratory failure is the most common cause of death.^[1]

Since its initial description in the late 1930s, there have been many significant advances in the management of CF. Current standard of care includes regular chest physiotherapy, maximization of nutritional status, careful screening for and treatment of comorbid conditions, and prompt and aggressive treatment of respiratory infections.^[2,3] The result of this comprehensive management has been a consistent increase in overall survival; it is also associated with increasing burden of care. The most recent patient registry data from the US Cystic Fibrosis Foundation (CFF) shows a median life expectancy approaching 38 years of age (Figure 1).^[4]

(Enlarge Image)

Figure 1.

Improved survival in cystic fibrosis.

Anti-infective therapy has evolved over the past 70 years to include formulations of intravenous, oral and inhaled medications. These therapies are tailored to individual patients based on several clinical factors, including the presence of specific chronic airway pathogens, severity of acute exacerbation and underlying chronic lung disease, and need for inpatient versus outpatient treatment. There are also several anti-infective strategies for the chronic maintenance of lung health. A comprehensive review of the pathophysiology and management of infections in CF has been published.^[3] Furthermore, recent US and UK guidelines are available, which outline current standards of antibiotic therapy.^[5,6] The purpose of this article is to review recent knowledge on the antibiotic treatment of pulmonary infections in CF, with particular emphasis on drugs used for the treatment of clinically important and emerging pathogens.

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Table 1. Appropriate antibiotic therapy reduces bacterial load but is unable to completely clear pathogenic organisms
	CF lung infection	General concept of susceptibility
Bacterial isolate	Pseudomonas aeruginosa (sputum)	P. aeruginosa (bloodstream)
Bacterial density	100,000,000 CFU/g	100,000 CFU/ml
Susceptibility method	Microdilution	Microdilution
Susceptibility result	Tobramycin MIC = 2 mg/l	Tobramycin MIC = 2 mg/l
Intravenous treatment	Tobramycin × 14 days Ceftazadime × 14 days	Tobramycin × 7 days
Pharmacokinetics (peak serum concentration)	40 mg/l	40 mg/l
Antimicrobial effect (culture at end of treatment)	2,500,000 CFU/g	Organism not detected

CF: Cystic fibrosis; CFU: Colony-forming unit.
Data provided courtesy of Sam Moskowitz, MD, Massachusetts General Hospital, MA, USA.

Table 2. Commonly used antibiotics in cystic fibrosis*.
Antibiotic	Pediatric dose (mg/kg/day)	Adult maximum dose (dose/day)	Interval (h)	Side effects
Intravenous
Amikacin^‡	30–45	No max	8–24	Nephrotoxicity, ototoxicity and vestibular dysfunction
Gentamicin^‡	10–15	No max	8–24	Nephrotoxicity, ototoxicity and vestibular dysfunction
Tobramycin^‡	10–15	No max	8–24	Nephrotoxicity, ototoxicity and vestibular dysfunction
Ceftazidime	150	6 g	8	Rash, fever and diarrhea
Cefepime	150	6 g	8	Rash, fever and diarrhea
Piperacillin–tazobactam	400	16 g	6	Rash, fever, diarrhea and hypersensitivity syndrome
Ticarcillin–clavulanate	400–600	12–18 g	4–6	Rash, fever, diarrhea and hypersensitivity syndrome
Meropenem	120	6 g	8	Rash, fever, nausea, emesis and diarrhea
Imipenem–cilastatin	100	2 g	6	Rash, fever, nausea, emesis, diarrhea and seizures (risk of side effects often limits use)
Aztreonam	200	8 g	6	Rash, fever and diarrhea
Ciprofloxacin	30	1.2 g	8–12	Rash, diarrhea, arthralgia and tendon rupture
Levofloxacin	10–20	750 mg	12–24	Rash, diarrhea, arthralgiav and tendon rupture
Nafcillin	200	12 g	4–6	Rash, fever, diarrhea and thrombophlebitis
Teicoplanin^‡	10–20	6–12 g	12–24	Rash, fever, nephrotoxicity and ototoxicity
Vancomycin^‡	40–60	None	6–12	Nephrotoxicity, red man syndrome, rash and fever
Clindamycin	30–40	2.7 g	6–8	Rash, diarrhea, Clostridium difficile colitis and nausea
Trimethoprim/sulfamethoxazole^§	10–20	1280 mg	6–12	Rash, diarrhea, nausea, hyperkalemia, thrombocytopenia, renal dysfunction and serum sickness
Linezolid	20–30	1.2 g	8–12	Diarrhea, nausea, rash, thrombocytopenia, lactic acidosis, risk for serotonin syndrome and vision changes
Tigecycline	NA	100 mg	12	Rash, nausea, emesis, diarrhea, pancreatitis and dental staining
Quinupristin/dalfopristin	22.5	None	8	Rash, arthralgia, myalgia and thrombophlebitis
Colistin^¶	5–8	480 mg	8	Nephrotoxicity, peripheral neuropathy and pruritus
Chloramphenicol^#	60–80	4 g	6	Blood dyscrasias, rash and gray baby syndrome
Fosfomycin	100–200	12–15 g	8	Rash, nausea and diarrhea
Oral
Amoxicillin/clavulanic acid	45–90	4 g	12	Rash and diarrhea
Dicloxacillin	100	2 g	6	Rash and diarrhea
Cephalexin	50–100	4 g	6–8	Rash and diarrhea
Cefdinir	14	600 mg	12–24	Rash, diarrhea and red-orange stools
Trimethoprim/sulfamethoxazole^§	10–20	1280 mg	6–12	Rash, diarrhea, nausea, hyperkalemia, thrombocytopenia, renal dysfunction and serum sickness
Clindamycin	30	1.8 g	6–8	Rash, diarrhea, C. difficile colitis and nausea
Ciprofloxacin	40	2 g	12	Rash, diarrhea, arthralgia and tendon rupture
Levofloxacin	10–20	750 mg	12–24	Rash, diarrhea, arthralgia and tendon rupture
Doxycycline^**	4	200 mg	12–24	Rash, photosensitivity, dental staining and bone growth retardation
Minocyclin^**	4	200 mg	12	Rash, dental staining, photosensitivity and bone growth retardation
Linezolid	20–30	1.2 g	8–12	Diarrhea, nausea, rash, thrombocytopenia, lactic acidosis, risk for serotonin syndrome and vision changes
Chloramphenicol^#	50–100	4 g	6	Blood dyscrasias, rash and gray baby syndrome
Inhaled
Tobramycin	300–600 mg	600 mg	12	Bronchospasm, hoarseness, sore throat, cough, dyspnea, voice disturbance and tinnitus
Amikacin^‡‡	500–1500 mg	1500 mg	12	Bronchospasm, hoarseness, sore throat, cough, dyspnea, voice and taste disturbance and tinnitus
Colistin^¶‡‡	75–150 mg	300 mg	12	Bronchospasm, cough, dyspnea, sore throat and taste disturbance
Aztreonam^‡‡	1000–2000 mg	2000 mg	12	Bronchospasm, cough, dyspnea and taste disturbance

*All doses assume normal renal and hepatic function. Consult a specialized drug reference for dosage adjustment if function is impaired. Dose and/or interval may require adjustment.
^‡Empiric starting doses only. Adults dosed at pediatric dosing range without a maximum capped dose. Adjust dose per therapeutic drug monitoring.
^§Dose based on trimethoprim component.
^¶Dose expressed as mg of colistin base. Some countries dose colistin in IU. 1 mg is approximately equal to 12,500 IU. Colistin is also referred to as colistimethate sodium, colistin methanesulfonate, colistin sulfomethate, pentasodium colistin methanesulfonate and colomycin in the literature.
^#Empiric starting doses only. Adjust dose per therapeutic drug monitoring.
^**Children older than 8 years of age.
^‡‡Prepared off-label from commercially available intravenous products.
NA: Not available.

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